      Document 0117
 DOCN  DRG0117
 UNIQUE IDENTIFIER        DRG-0130
 NAME OF SUBSTANCE        Valproic Acid [USAN 1996]
 REGISTRY NUMBER          99-66-1
 STANDARD CHEMICAL NAME   Pentanoic acid, 2-propyl- [USAN 1996]
 SYNONYMS                 Depakene [USAN 1996]
 SYNONYMS                 Propylvaleric acid [USAN 1996]
 SYNONYMS                 Dipropylacetic acid [PDR 1995]
 SYNONYMS                 Mylproin [Merck Index 1989]
 SYNONYMS                 2-Propylpentanoic acid [PDR 1995]
 PROTOCOL ID NUMBERS      NIAID ACTG 191
 SECONDARY SOURCE ID      44089 [USAN 1996]
 PHARMACOLOGICAL ACTION   MODE OF ACTION: Valproic acid competitively
                          inhibits GABA transaminase, thereby
                          increasing the brain gamma-aminobutyric acid
                          (GABA) level. Increased GABA levels may
                          protect the organism against seizure. The
                          drug is rapidly absorbed after oral
                          administration and dissociates to the
                          valproate ion in the gastrointestinal tract.
                          Peak plasma concentrations of valproate ions
                          are observed 1 to 4 hours after a single oral
                          dose of valproic acid. A slight delay in
                          absorption may occur when the drug is taken
                          with food, but total absorption is not
                          affected. Valproate is primarily metabolized
                          in the liver. The major metabolic routes are
                          glucuronidation, mitochondrial beta
                          oxidation, and microsomal oxidation.
                          Metabolites are eliminated primarily in the
                          urine. Valproate is highly bound (90 percent)
                          to plasma proteins in the therapeutic range;
                          however, protein binding is
                          concentration-dependent and decreases at high
                          valproate concentrations. Binding is variable
                          among patients and may be affected by fatty
                          acids or by highly bound drugs such as
                          salicylate. The therapeutic range is
                          considered to be 50-100 mcg/ml total
                          valproate although some patients may be
                          controlled at lower or higher plasma
                          concentrations. The plasma half-life of
                          valproate is generally 6-16 hours. [PDR 1995]
                          [CHEMLINE]
 DISEASES STUDIED/TREATED Possible inhibition of the metabolic
                          inactivation of zidovudine (AZT), resulting
                          in a longer duration of AZT effects in the
                          body [Int Conf AIDS 1992 Jul 19-24;8(3)
                          (abstract no PuB 7307]
 CLASSIFICATION CODE      Anticonvulsant [USAN 1996]
 CLASSIFICATION CODE      Antiepileptic [Merck Index 1989]
 OTHER MAJOR USES         Indicated for use as sole and adjunctive
                          therapy in the treatment of simple and
                          complex seizures [PDR 1995]
 SUBSTANCE INTERACTIONS   May potentiate the CNS depressant activity of
                          alcohol. Concomitant use with phenobarbital
                          may result in severe CNS depression.
                          Concomitant administration of valproic acid
                          with drugs that exhibit extensive protein
                          binding (e.g., aspirin, carbamazepine,
                          dicumarol, and phenytoin) may result in
                          alteration of serum drug concentrations.
                          Concomitant use with other antiepileptic
                          drugs should be monitored. [PDR 1995]
 ADVERSE EFFECTS          Possible serious hepatotoxicity or hepatic
                          failure, often preceded by nonspecific
                          symptoms such as loss of seizure control,
                          malaise, weakness, lethargy, facial edema,
                          anorexia, and vomiting. Other adverse effects
                          include CNS effects such as sedation, tremor
                          (may be dose-related), ataxia, headache,
                          nystagmus, diplopia, asterixis, spots before
                          eyes, dysarthria, dizziness, and
                          incoordination; abnormal thyroid function;
                          hyperammonemia; and thrombocytopenia. [PDR
                          1995]
 CONTRAINDICATIONS        Contraindications include hepatic disease or
                          significant hepatic dysfunction; known
                          hypersensitivity to valproic acid. Possible
                          contraindication: pregnancy (should be used
                          in pregnant women only if absolutely
                          essential for control of seizures). [PDR
                          1995]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: A carboxylic acid with
                          anticonvulsant properties [PDR 1995]
 CHEMICAL/PHYSICAL DATA   PHYSICAL DESCRIPTION: Colorless liquid [PDR
                          1995]
 CHEMICAL/PHYSICAL DATA   MOLECULAR FORMULA: C8H16O2 [USAN 1996]
 CHEMICAL/PHYSICAL DATA   MOLECULAR WEIGHT: 144.21 [USAN 1996]
 CHEMICAL/PHYSICAL DATA   ELEMENTAL COMPOSITION: C66.62%, H11.19%,
                          O22.19% [Merck Index 1989]
 CHEMICAL/PHYSICAL DATA   SOLUBILITY: Slightly soluble in water, very
                          soluble in organic solvents [PDR 1995]
 CHEMICAL/PHYSICAL DATA   PHYSICAL COMMENT: The pKa is 4.8 [PDR 1995]
 CHEMICAL/PHYSICAL DATA   MELTING POINT: 120-130 C [Merck Index 1989]
 SUBSTANCE DELIVERY DATA  DOSAGE FORM: Syrup, 250 mg capsules. [PDR
                          1995]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY: Oral. [PDR 1995]
 SUBSTANCE DELIVERY DATA  STORAGE: Store capsules at 59-77 F (15-25 C);
                          store syrup below 86 F. [PDR 1995]
 MANUFACTURERS            Abbott Laboratories
 REFERENCES               Lertora JJ, Rege AB, Greenspan DL, Akula S,
                          George WJ, Hyslop NE Jr, Agrawal KC.
                          Pharmacokinetic interaction between
                          zidovudine and valproic acid in patients
                          infected with human immunodeficiency virus.
                          Clin Pharmacol Ther. 1994 Sep;56(3):272-8.
 REFERENCES               Simon G, Moog C, Obert G. Valproic acid
                          reduces the intracellular level of
                          glutathione and stimulates human
                          immunodeficiency virus. Chem Biol Interact.
                          1994 Jun;91(2-3):111-21.
 REFERENCES               Lertora J, Akula S, Greenspan D, Rege A,
                          Agrawal K, George W, Hyslop N. Valproic acid
                          inhibits zidovudine glucuronidation in
                          patients with HIV infection. Int Conf AIDS.
                          1992 Jul 19-24;8(3):100 (abstract no. PuB
                          7307).
 REFERENCES               Agrawal KC, DiPiazza NJ, Aggarwal SK.
                          INHIBITION OF HUMAN HEPATIC GLUCURONOSYL
                          TRANSFERASE (GT) ACTIVITY TO ALTER ZIDOVUDINE
                          (AZT) METABOLISM (MEETING ABSTRACT) Proc Annu
                          Meet Am Assoc Cancer Res. 1992;33:A2389.
 ENTRY MONTH              9112
 LAST REVISION DATE       951004
 

SOURCE: National Library of Medicine, Bethesda, MD.  Distributed by AEGIS.
